Born in Williamsburg, Virginia, Blair was a member of a prominent Virginia family. His father served on the Virginia Council and was for a time acting Royal governor. His granduncle, James Blair, was founder and first president of the College of William & Mary. Blair attended William & Mary, receiving an A.B. in 1754. In 1755 he went to London to study law at the Middle Temple. Returning home to practice law, he was quickly thrust into public life, beginning his public career shortly after the close of the French and Indian War with his election to the seat reserved for the College of William and Mary in the House of Burgesses (1766–70). He went on to become clerk of the Royal Governor’s Council, the upper house of the colonial legislature (1770–75).

Blair originally joined the moderate wing of the Patriot cause. He opposed Patrick Henry’s extremist resolutions in protest of the Stamp Act, but the dissolution of the House of Burgesses by Parliament profoundly altered his views. In response to a series of Parliamentary taxes on the colonies, Blair joined George Washington and others in 1770 and again in 1774 to draft nonimportation agreements which pledged their supporters to cease importing British goods until the taxes were repealed. In the latter year he reacted to Parliament’s passage of the Intolerable Acts by joining those calling for a Continental Congress and pledging support for the people of Boston who were suffering economic hardship because of Parliament’s actions.

When the Revolution began, Blair became deeply involved in the government of his state. He served as a member of the convention that drew up Virginia’s constitution (1776) and held a number of important committee positions, including a seat on the Committee of 28 that framed Virginia’s Declaration of Rights and plan of government. He served on the Privy Council, Governor Patrick Henry’s major advisory group (1776–78). The legislature elected him to a judgeship in the general court in 1778 and soon thereafter to the post of chief justice. He was also elected to Virginia’s high court of chancery (1780), where his colleague was George Wythe, later a fellow delegate to the Constitutional Convention. These judicial appointments automatically made Blair a member of Virginia’s first court of appeals. In 1786, the legislature, recognizing Blair’s prestige as a jurist, appointed him Thomas Jefferson’s successor on a committee revising the laws of Virginia.

On September 24, 1789, Blair was nominated by President George Washington to the Supreme Court of the United States. He was confirmed by the United States Senate on September 26, 1789, and received his commission on September 30. Blair resigned on October 25, 1795, and died in Williamsburg, five years later, aged 68.  Blair Street in Madison, Wisconsin is named in his honor.  Blair was a Freemason. He was named Grand Master of Freemasons in Virginia under the newly organized Grand Lodge of Virginia in 1778.